Transdermal Cannabidiol Delivery for Alcohol-Induced Neurodegeneration

描述(由申请人提供)：酒精使用障碍(AUD)的治疗，通常被称为酒精中毒，一直受到酒精混杂的药理作用和成瘾的复杂病因的阻碍。人们过度饮酒的原因多种多样，而针对更多这些原因的方法将比只针对一个方面的方法获得更大的商业成功。过量饮酒会导致大脑发生许多变化，导致成瘾，包括进行性神经退化和执行功能受损，以及导致戒断诱导的负面情绪的依赖。然而，在FDA目前批准的三种治疗过度饮酒的药物中，没有一种药物能治疗神经变性、戒断或焦虑。尽管最近在许多神经退行性疾病模型中具有神经保护作用的一类药物取得了成功，但大麻类药物却取得了成功。有趣的是，这类药物，特别是大麻二醇(CBD)，也具有抗惊厥(戒断)和抗焦虑特性，使其成为治疗AUDS的理想候选药物。由于缺乏合适的给药方法，对大麻素类化合物的研究一直很少。口服给药通常是首选给药途径，但CBD的口服生物利用度仅为6%左右。因此，将使用经皮给药途径，以提供相当大的血浆CBD水平，并增加控释给药的便利性。这项建议将通过确定(1)大麻二醇经皮给药是否可以防止已建立的酗酒大鼠模型中酒精诱导的神经变性，来检验大麻素类药物大麻二醇经皮给药可能防止酒精神经和行为病理的总体假设。为此，我们将改进CBD的经皮给药，并通过检测退变细胞的荧光Jade B标记和通过检测神经前体/干细胞增殖的标记来检测其对细胞死亡和细胞出生的影响，以及(2)在酗酒大鼠模型中，经皮给药大麻二醇是否可以防止酒精诱导的行为病理。与AUDS相关的行为病理包括对药物的专注(坚持不懈)和因停药而产生的负面情绪(焦虑)。这两种行为都可能促使药物寻求缓解这些症状，因此是预防复发的主要候选对象。因此，在这个目的中，我们研究了CBD经皮给药对戒断严重程度的影响，包括癫痫发作，在高架Plus迷宫上的戒断诱导的焦虑，以及在酗酒后的Morris水迷宫上的持久性行为。超过8.5%的人口符合酒精使用障碍(AUD)的诊断标准，酒精使用和滥用是该国主要的公共卫生问题之一。目前批准的药物治疗只针对成瘾的渴望方面，这一方法已经使很大一部分酗酒者失败。因此，酒精中毒的治疗将受益于针对酒精中毒的多个方面的药理学方法：神经退化、戒断和焦虑。在适当的给药系统中给予大麻二醇具有这些好处，作为寻找新的酒精中毒药物疗法的主要候选药物。

DESCRIPTION (provided by applicant): Treatment of alcohol use disorders (AUDs), commonly referred to as alcoholism, has been hampered by alcohol's promiscuous pharmacological effects and the complex etiology of addiction. People drink in excess for a variety of reasons, and an approach that targets more of these reasons will have greater commercial success than an approach that only targets a sole aspect. Excessive consumption of alcohol results in many changes in the brain that contribute to the development of addiction including progressive neurodegeneration and impaired executive function, and dependence that leads to withdrawal-induced negative affect. However, of the three drugs currently approved by the FDA for the treatment of excessive alcohol consumption, none address neurodegeneration, withdrawal or anxiety. Whereas recently success has been seen in a class of drugs that are neuroprotective in many neurodegenerative disease models, the cannabinoids. Intriguingly, this class of drugs, and specifically cannabidiol (CBD), also has anticonvulsant (withdrawal) and anxiolytic properties that make it an ideal candidate for the treatment of AUDs. The cannabinoid class of compounds has been minimally studied because of the lack of a suitable drug delivery method. Oral delivery of drugs is usually the preferred administration route, however the oral bioavailability of CBD is only about 6%. Therefore, the transdermal delivery route will be used in order to provide substantial plasma CBD levels with the added convenience of controlled release delivery. This proposal will test the overall hypothesis that transdermal delivery of a cannabinoid, cannabidiol, may protect against alcoholic neural and behavioral pathologies by determining (1) if transdermal delivery of cannabidiol can prevent alcohol-induced neurodegeneration in an established rat model of binge drinking. In this aim, we will refine transdermal delivery of CBD and examine its effects on both cell death via examination of Fluoro-Jade B labeling of degenerating cells and cell birth via examination of labeling of neural progenitor/stem cell proliferation and (2) whether transdermal delivery of cannabidiol can prevent alcohol-induced behavioral pathology in a rat model of binge drinking. Behavioral pathologies associated with AUDs include preoccupation with the drug (perseveration) and negative affect (anxiety) as the result of withdrawal from the drug. Both behaviors may then drive drug seeking to alleviate these symptoms and thus are leading candidates as targets of relapse prevention. Therefore, in this aim, we examine the effect of transdermal delivery of CBD on withdrawal severity including seizures, withdrawal- induced anxiety on the Elevated Plus Maze and perseverative behavior on the Morris Water Maze following binge alcohol exposure. With over 8.5% of the population meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol use and abuse are one of the nation's major public health problems. Currently approved pharmacological treatments have only targeted the craving aspect of addiction, an approach that has failed a large portion of alcoholics. Thus, the treatment of alcoholism would benefit from a pharmacological approach designed to target multiple aspects of alcoholism: neurodegeneration, withdrawal and anxiety. Cannabidiol administration in the appropriate delivery system has these benefits as a lead candidate in the search for novel alcoholism pharmacotherapies.